Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation.
Dhiren F PatelTeresa PeiróNicoletta BrunoJuho VuononvirtaSamia AktharFranz PutturChloe J PyleKornelija SuveizdyteSimone A WalkerAran SinganayagamLeo M CarlinLisa G GregoryClare M LloydRobert J SnelgrovePublished in: Science immunology (2020)
Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.
Keyphrases
- dendritic cells
- allergic rhinitis
- oxidative stress
- regulatory t cells
- transcription factor
- immune response
- bone marrow
- induced apoptosis
- case report
- cerebrospinal fluid
- peripheral blood
- nk cells
- signaling pathway
- atopic dermatitis
- quality improvement
- bone mineral density
- cell proliferation
- climate change
- health risk
- endoplasmic reticulum stress
- heavy metals